Method of coating particles and coated spherical particles

ABSTRACT

A microparticle comprising an active substance which is a central core made of liquid, gaseous or solid particle of regular or irregular shape, and the method for entrapping said active substance in a coating material which is conformationally distributed on said active substance and has a thickness ranging from the thickness of a monomolecular layer to about 100 μm. These compositions are useful for applications that require protection, prolonged release, taste masking, improved stability, altered handling behavior, altered surface properties including particle wettability, and other desirably altered properties.

FIELD OF THE INVENTION

This invention relates to the art of coating substances in the solidliquid or gaseous state, particularly solid particles and solidarticles, especially solid articles with complex geometries or finiteinternal porous structures. In particular, this invention relates to amethod for embedding or coating preformed particles or articles in solidliquid or gaseous state within a coating material to producemicroparticles having an active substance entrapped in a layer ofcoating material. Such compositions are useful for applications thatrequire protection, prolonged release, controlled release, tastemasking, improved stability, altered handling behavior, altered surfaceproperties including particle wettability, and other desirably alteredproperties.

BACKGROUND OF THE INVENTION

Many techniques for coating substances have been developed over theyears. Nevertheless, there is a persistant need for new techniques ableto coat a wide range of preformed solid particles. The reasons for thisneed are numerous. For instance, new applications for solid particulatematerials and articles are developed consistently thereby requiringimproved coating methods. Also, new coating materials are developed andrequire for their application new coating protocols. Furthermore, manyexisting coating protocols require the use of solvents which are oftentoxic or hazardous either to the environment, to personnel involved in agiven particle coating protocol, or to the user of the particle. Thelatter situation arises when the final coated particle retains a finiteamount of solvent(s) used in the coating of coated solid particles orarticles. Further, solvents used in conventional solid particle orarticle coating processes may attack and partially dissolve the solidparticles or articles being coated thereby altering properties of thesolid particles or articles in some manner. Additionally, solvent-basedcoating formulations may cause mean size of particulate compositionsbeing coated to increase measurably due to agglomeration caused by thenature of the solvent-based coating at the time of application.

A preponderance of current solid particle and article coating protocolsinvolve deposition of liquid coating formulations on the surface(s) ofthe solid compositions being coated followed by solidification of saidcoating formulations. Solidification may occur because solvent isremoved from the applied coating formulations, because the initiallyliquid coating formulations solidify due to cooling (e.g., theycrystallize or pass below a glass transition temperature of the coatingformulation during a cooling step), because initially liquid coatingformulations are polymerized to a solid during the coating protocol, orbecause of a combination of these factors.

Supercritical fluids (SCF) in general, and supercritical carbon dioxide(SC CO₂) in particular, are prime vehicles by which improved coatingtechnology can be developed and applied. They are protrayed asenvironmentally friendly fluids which can be used for a variety ofeconomically useful purposes.

U.S. Pat. No. 4,598,006 discloses a method for impregnating athermoplastic polymer with an impregnation material such as a fragranceor pest control agent or pharmaceutical composition wherein theimpregnation material is dissolved in a volatile swelling agent for thethermoplastic polymer, said swelling agent being maintained at or nearsupercritical conditions.

U.S. Pat. No. 5,043,280 discloses a method and apparatus for themanufacture of a product having a substance embedded in a carrier thatinvolves the use of a supercritical gas or supercritical fluid (SCF).The method consists of passing a liquid that contains a substance andcarrier through a nozzle into a chamber loaded with a SCF therebyforming a gaseous mixture of the SCF and liquid medium, followed byseparating the gaseous mixture of SCF and liquid medium to produce asterilized product comprising a substance embedded in a carrier.

SUMMARY OF THE INVENTION

The invention relates to microparticles comprising an active substance,preferably an active substance in the form of a solid particle or aninert porous solid particle having absorbed therein an active substancein the liquid state or dissolved in a suitable solvent, the activesubstance or the inert solid being entrapped within a coating includinga layer of a coating material. The microparticles are characterized inthat the layer of coating material is conformationally distributed onthe active substance and has a thickness ranging from the thickness of amono-molecular layer to about 100 μm, preferably to about 40 μm.Preferably, the active substance found in the microparticles of thepresent invention is a central core comprising a liquid, gaseous orsolid particle of regular or irregular shape. In the case of a solidparticle of irregular shape, the coating of the microparticles of thepresent invention follows the surface of the particles being coated,including internal pores and crevices. The particle size of themicroparticles of the present invention ranges in diameter from 1 nm toabout 1 cm, preferably from 20 nm to 100 μm.

In another embodiment of the present invention, the coating of themicroparticles of the present invention comprises a plurality of layersof identical or different coating materials. The thickness of each layermay be identical or different.

Also within the scope of the present invention is a compositioncomprising a plurality of microparticles of even or uneven sizedistribution. The microparticles comprise an active substanceconformationally entrapped within a layer of a coating substance havinga thickness ranging from the thickness of a monomolecular layer to about100 μm. Preferably, the active substance of the microparticles formingthe composition of the present invention is a central core comprising asolid particle.

The invention also relates to a process for entrapping an activesubstance, preferably a solid particle or an inert porous solid particlehaving the active substance absorbed therein, in a coating material. Theprocess comprises suspending an active substance in a supercriticalfluid containing a coating material dissolved therein under conditionswhich cause substantially no swelling and/or dissolution effect on theinert porous solide particle or the active substance if the activesubstance is in the solid state. The temperature and/or pressure of thesupercritical fluid is then gradually reduced under controlledconditions to reduce the solubility of the coating material in thesupercritical fluid to cause the coating material to be deposited ontothe active substance. Particularly, the process is characterized in thatthe active substance is in the form of liquid droplets, gas, preferablyin the form of solid particles or in the form of a liquid in which thesolid substance is being dissolved, the liquid absorbed in a poroussolid substrate. The liquid droplets, gas or preferably the solidparticles are constantly agitated or stirred during their exposure tothe supercritical fluid containing the coating material dissolvedtherein. More particularly, the active substance is a solid particle andthe conditions under which the solid particle is coated by the coatingmaterial are chosen to maintain the physical integrity of the solidparticle in other words to avoid solubilization of the solid particlethroughout its contact with the SCF.

The process of the invention can also comprise further step in which thecoating material deposited onto the active substrate is cured in acontrolled manner.

In practising the process of the present invention, the active substanceand the coating material can be placed in an autoclave which is thenfilled with a supercritical fluid under conditions of temperature andpressure required to dissolve the coating material in the supercriticalfluid. Alternatively, the active substance can be placed in a autoclavewhich is then filled with a supercritical fluid containing the coatingmaterial already dissolved therein.

The present invention also relates to an apparatus for depositing acoating material dissolved in a supercritical fluid onto an activesubstance. The apparatus comprises a reservoir/reaction chamber capableof receiving and maintaining a gas under supercritical conditions, and apressurizable reaction chamber in fluid communication with thereservoir/reaction chamber. The reaction chamber comprises stirringmeans to suspend the active substance when the supercritical fluid isintroduced in the reaction chamber. The apparatus also comprises meansfor controlling the temperature and/or the pressure in the reactionchamber. Preferably, the stirring means is an agitator including amagnetic transmissions stirrer.

Particularly, the apparatus of the present invention can furthercomprise reservoir means in fluid communication with the supercriticalgas condenser for dissolving the coating material in the supercriticalfluid.

The final result is coated active substances in tire form of solids,liquids, gases, particles or articles with desireable propertiesobtained without the use of usual organic solvent(s). The coated activesubstances have a controlled thickness and/or geometry of coatingmaterial and are isolated after the coating system is depressurized toatmospheric pressure and returned to room temperature if the coating wasdone at some temperature other than room temperature.

Particularly, the invention relates to the coating of preformed solidparticles or articles by controlled changes in a system that initiallycontains a mixture of a SCF and a coating material dissolved thereon.The mixture is maintained at temperature and pressure conditions underwhich the solid particles or articles are insoluble in the SCF. Thetemperature and/or pressure of the system is subsequently altered insuch a manner as to cause controlled precipitation and/orcrystallization of the coating material from the SCF phase onto thesurface of the exposed solid particles or articles thereby formingcoated solid particles or articles. The solid particles can be porousinert particles in which is absorbed an active substance dissolved in asolvent not miscible or having a substantially weak affinity for the SCFin which the coating substance is dissolved.

One of the important advantages of the process of the present inventionresides in the fact that the resulting microparticles are substantiallyfree of pores exposing the active material either in liquid, gaseous orsolid form, to external conditions. The reason for this is that sincethe active substance is not dissolved in the SCF, upon return to normalpression conditions, the SCF does not escape from the central core tocreate important channels in the coating material and if the activesubstance is a solid particle. The SCF only escapes from the thin layerof coating material and temperature and pression conditions can bevaried to promote a gradual escaping of the SCF from the coatingmaterial, thereby avoiding substantial pore formation. Also, because theprocess of the present invention does not require spraying of the activesubstance under which coating must be performed very quickly, andbecause the active substance is not solubilized in the SCF, it ispossible to successively apply multiple layers of either identical ordifferent coating materials onto the active substance. In order to doso, the temperature and pressure parameters of the SCF can be varied ina controlled manner to achieve desired dissolution and subsequentsolidifying of the coating material. dr

In the drawings:

FIG. 1 illustrates a complete schematic representation of a preferredembodiment of the apparatus of the invention;

FIG. 2A is a photograph of untreated bovine serum albumine;

FIG. 2B is a photograph of a bovine serum albumine treated with gelucire50/02;

FIG. 3 is a photograph of juvamine treated with gelucire 50/02;

FIG. 4 is a photograph of bovine serum albumine treated by Beeswax;

FIG. 5 is a photograph of hemoglobin treated with Beeswax;

FIG. 6 shows untreated juvamine and juvamine treated by Beeswax;

FIG. 7 is a photograph of juvamine shown in FIG. 6, 15 seconds afteraddition of a drop of water;

FIG. 8 is a photograph of juvamine shown in FIG. 6, 2 minutes afteraddition of a drop of water.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the method of this invention, coating materialsdissolved in a SCF are deposited in a controlled manner on the surfaceof active substances such as solutions of active substances, meltedactive substances, emulsions, solid particles or articles which areinsoluble in or unaffected by SCF, thereby producing the desiredcoating.

Coating materials

Preferred coating materials are materials soluble in a SCF (e.g.,supercritical CO₂) under conditions that do not substantially alter oraffect the substrate being coated or the material(s) being used ascoating material(s). Candidate coating materials include materialstypically generically classified as lipids. Specific examples are mono-di- and tri-glycerides of various fatty acids like monostearin,distearin, tristearin, monopalmitin, dipalmitin, tripalmitin,monolaurin, dilaurin, trilaurin, as well as various combinations ofthese and related fatty acid glycerides. Glycerides produced byacetylation of mono- or di-glycerides, or by hydrogenation of variousliquid glycerides to thereby produce solid fats (e.g., hydrogenatedvegetable oils of all types) are also candidates. Other candidate lipidsare fatty alcohols like stearyl alcohol and palmityl alcohol, fattyacids like stearic acid, palmitic acid, myristic acid, and lauric acid,and combinations of these materials with other lipids. Still othercandidate generic lipids are assorted waxes like beeswax, caranauba wax,paraffin waxes, or combinations, of these and other waxes with eachother or with the assorted glycerides mentioned previously. Still othercandidate lipid coating materials are cholesterol, various cholesterolderivatives, and various combinations of these lipids with variouscombinations of the aforementioned lipids known as glycerides, fattyacids, fatty alcohols, and waxes. Still other candidate coatingmaterials are lecithin, shellac, and natural or synthetic organicpolymers of assorted types.

Some of the substances which can be used as coating substances in thecontext of the present invention can require the use of an entrainersubstance for the solubilization into the SCF. An entrainer is asubstance that when dissolved in small amounts in a SCF greatlyincreases solubility of the material(s) being dissolved in the SCF, inthe present case, the coating material(s), without having substantialeffect on the SCF properties of the primary component of the SCF systemor density of the SCF system.

Specific nonlimiting examples of coating materials that often requirethe use of an entrainer include shellac, as well as natural or syntheticpolymers such as assorted polyester and polyanhydride polymers commonlyclassified as biodegradable. Such polymers include all poly(lactide)homopolymers and copolymers with glycolic acid as well as polyglycolidehomopolymer. Such polymers as well as their properties are described indetail in EP 052510, U.S. Pat. No. 3,887,699, EP 0548481 and U.S. Pat.No. 3 773 919. Poly(ε-caprolactone), poly(β-hydroxybutyrate),poly(hydroxyvalerate) and β-hydroxybutyrate-hydroxyvalerate copolymers.Other candidate coating materials that may require the use of anentrainer include a variety of polymers formed by free radicalpolymerization or polycondensation representative examples of whichinclude polystyrene, poly(methyl methacrylate), poly(vinyl chloride),polyvinyl alcohol, polyvinyl esters (like polyvinyl acetate or polyvinylphtalate), and polyvinyl pyrolidone, poly(dimethyl siloxane),polysulfone, assorted polyamides (or nylons), poly(ethyleneterephthlate), polyolefins like polypropylene, polyethylene and itscopolymers with acrylic or methacrylic acid or acrylate esters likemethyl methacrylate and butyl methacrylate, polysaccharides and theirderivatives such as cellulose, chitosan, carraghenane and theirderivatives.

Combinations of assorted coating materials can be applied either bysequential deposition of the different candidate coating materials underdifferent SCF operating conditions or, if different combinations ofcoating materials are deposited simultaneously, said deposition ofcombinations of materials occurs from a given SCF system underconditions where, prior to the deposition step, said combination ofcoating materials has measurable solubility in the SCF system being usedand during the coating material deposition step, said combination ofmaterials has equal affinity for the surface being coated so that onematerial is not deposited to the total exclusion of the othermaterial(s).

Supercritical fluids

In the case of supercritical CO₂ (SC CO₂), typical initial operatingconditions will be approximately 31 to 80° C. and pressures of 70 to 250bars, although higher values of either or both parameters can be used,provided, of course, that the higher values have no deleterious effecton the substrate being coated. With SCF systems other than SC CO₂,minimal operating temperatures and pressures will be those necessary toform a SCF with such systems. Ref. 2 specifies these conditions for anumber of materials commonly used as SCF. Tom and Debenedetti (Ref. 1)say that normally the term supercritical is reserved for fluids thatexist within the following approximate reduced temperature and reducedpressure range: 1.01<Tr<1.1 and 1.01<Pr<1.5, where T_(r), the reducedtemperature, is the ratio of the actual operating temperature (° K.) ofthe system to the critical temperature (° K.) of the material(s) thatserves as the SCF while P_(r), the reduced pressure, is the ratio of theactual operating pressure (can be specified in any established pressureunits) of the system to the critical pressure (same pressure units usedto specify the actual operating pressure) of the material(s) that servesas the SCF. In all cases, maximal operating temperatures and pressuresfor the purpose of this disclosure will be defined as those that beginto cause measurable undesireable alteration of properties of thesubstrate(s) being coated. These maximal operating conditions normallyare conditions that cause melting of the substrate, in case preformedsolid particles are used, chemical degradation of the substrate, or someother undesireable change in property of the substrate. The SCF used mayor may not contain an entrainer. As noted above, an entrainer is definedas a substance deliberately added to a SCF system in small amounts inorder to enhance solubility of a given substance(s) in said SCF system.When an entrainer is present in a small amount in the SCF (e.g., <5%),an amount so small that its presence has essentially no effect on theconditions needed to enter the supercritical state of the primarycomponent of the SCF system, it greatly enhances solubility propertiesof the coating material(s) in the chosen primary SCF component.Candidate entrainers include but are not limited to ketones, alcohols,esters and chlorinated solvents, as Nell as other well recognizedorganic solvents and plasticizers. Entrainers are used in cases wherethe candidate coating material(s) has little solubility in the preferredSCF.

Substances to be coated

The active substances to be coated using the concept of the presentinvention can be either liquids, solids or gases but are preferablyliquids and solids. The only requirement is that these substances be orhave the possibility to be rendered insoluble in the SCF in conditionsrequired to dissolve the coating material.

Examples of active substances which can be coated in accordance with thepresent invention include organic and inorganic compounds and peptideswhich find applications in pharmaceutical compositions, agrochemicalcompositions, human and animal food compositions, imaging compositions,ink compositions, cosmetic compositions, fragrance compositions,adhesive compositions and the like. Particularly, preferred arepharmaceutical compositions which may require a coating either to maskthe taste or to enable sustained release of active substances embeddedin biodegradable polymers such as those mentioned above. Preferredactive substances include cimetidine, ranitidine, ibuprofen,acetaminophen, erythromycin, LHRH analogs such as buserelin, deslorelin,gonadorelin, goserilin, histrelin, leuprorelin, nafarelin ortriptorelin, pamoate, tannate, stearate or palmitate of a naturallyoccurring or synthetic peptide comprising from 3 to 45 amino acidsincluding LHRH, somatostatine, GH-RH or calcitonine . Other activesubstances include neurotrophic factor, ciliary neurotrophic factor,fibroblast growth factor, glial derived neurotrophic growth factor,brain derived neurotrophic factor nerve growth factor, vaccines,insuline, morphine and its derivatives and antibiotics.

In the event the substance to be coated is a solide particle, a widevariety of solid particles can be coated using the process of theinvention.

Examples are powders formed by crystallization, precipitation,pyrolysis, or evaporation of solvent from a solution that initiallycontained a dissolved solute, powders formed by grinding, milling,crushing, or any other mechanical size reduction process, powders formedby polymerization of monomers to form polymeric particles, powdersformed by granulation, prilling, and encapsulation techniques includingspray drying, hot melt processing, and extrusion-coextrusion processing,naturally occurring powders such as clays and inorganic pigments, andpowders formed by any other means. A significant feature of the processof the present invention is that it can be used to coat particles of awide range of geometries including particles of very regular andirregular geometry. The process can be used to coat perfect spheres,highly regular but nonspherical crystals having a wide range ofcharacteristic crystal habits (e.g., cubic, octahedronal, triclinic,etc.), and highly irregular particles typical of those formed by byconventional size reduction processes. Porous solid particles andarticles are additional candidate substrates to be coated by the processdisclosed herein because the process involves controlled deposition of acoating by "condensation", precipitation, or crystallization of theintended coating material on the surface of the solid particles andarticles directly from the supercritical state so that there is noconcern about a viscous coating solution formed with conventionalsolvents adequately penetrating the pores and crevices of the substanceto be coated. Indeed, a feature of the coating technology disclosed inthis application is the ability of this technology to deposit aconformational coating. That is, a coating that follows the surface ofthe particle(s) or article(s) being coated including internal pores andcrevices. Further, coatings composed of different coating materials canbe deposited in layers onto the external and internal surfaces of solidparticles and articles desired to be coated, said coatings ranging inthickness from molecular dimensions up to macroscopic dimensions,preferably from the thickness of a mono-molecular layer to about 100 pm,preferably to about 40 μm.

In one of the applications of the present invention, a porous solidparticle is used to allow coating of an active substance which forexample cannot be made solid at the desired temperature. In thesesituations, the active substance is usually either in the liquid stateor for instance dissolved in a solvent which has no affinity for theSCF. The active substance is abs orb ed in the porous solid particle. Ifthe amount of liquid absorbed on the porous solid particle is such thatthe strutural integrity of the particle can be maintained for at least alimited period of time of about 30 minutes to 4 hours. The porousparticle can be coated using the process of the present invention. Theabsence of affinity or miscibility of the liquid containing the activesubstance for the SCF further maintains this liquid in the poroussubstrate and avoids deep penetration of the SCF in the pores of thesubstrate. Once the porous substrate has been coated using the processof the invention, the active substance is trapped in the solid substrateand is released from it as the coating dissolves.

An additional feature of the coating process disclosed herein is that itcan be used to deposit, as a coating on a solid substrate, a specificfraction of material from a candidate coating material that is inreality a complex mixture of different components and not a singlecomponent material. This type of precise deposition of coating materialis something that is vertually impossible to do by other coatingtechniques. Many, if not most, candidate coating materials in commercialuse are known to be complex mixtures of various substances. Nonlimitingexamples include natural materials like fats and waxes, materialsderived from natural materials like hydrogenated fats, and syntheticmaterials like paraffin waxes. Other materials often sold as essentiallysingle component materials may contain up to 5-10% of assorted othercomponents often classified as impurities, it being well known thatproduction of absolutely pure materials for commercial use is generallya prohibitively costly task for commercial coating processes. Theassorted substances present in many materials, such as those mentionedabove, affect properties of the coated material in some manner.Accordingly, a SCF pre-extraction step under a specific set of operatingconditions can be carried out in order to selectively remove assortedcomponents of a candidate coating material deemed to be undesireable fora planned application thereby providing a precisely purified materialthat can be used as the coating material. Remarkably, this step can beconveniently carried out immediately before deposition of the coatingmaterial on a substrate is made to occur, so there is no question thatthe coating material is properly purified at the time it is deposited ona substrate. Another possibility is to use a specific set of SCFoperating conditions to selectively extract very specific component(s)from a complex mixture and subsequently cause said component(s) todeposit on a substrate thereby producing a coating that is made up onlyof the specific selected component(s).

General outlines of the process of the invention

Deposition of a coating by the process disclosed herein involvesaltering the temperature and pressure of a SCF in which the desiredcoating material(s) is dissolved. This alteration is carried out in acontrolled manner so that the desired coating material(s) eithercrystallizes on the surface of the substrate being coated orprecipitates there. The process disclosed herein is not based on rapidprecipitation, with or without subsequent crystallization, of materialsinitially dissolved in a SCF, to form free or self-standing smallparticles containing a combination of active substance or carriermaterial. This type of configuration, if it occurs, is the result ofimproper system operating conditions for deposition of the intendedcoating material(s). The process disclosed here is based on thecontrolled deposition of coating material(s) on the liquid droplets ofan emulsion, on a volume of gaseous particles or on the external andinternal surfaces of preformed solid particle(s) and article(s).

In the case of solid particles, the molecular interactions orattractions of dissolved solutes for solid surfaces are used toinitially attract and guide the coating molecules, initially dissolvedin the SCF system used to the surface being coated. This phenomenon inconventional liquid/solid and gas/solid systems is known as adsorption.The SCF containing the dissolved coating material(s) can be viewed as asolution, perhaps a nonconventional solution since the solute isdissolved in a SCF, but nevertheless a solution in which the coatingmaterial(s) is molecularly dissolved and hence, a solution from whichsolute adsorption can occur to thereby form a coating which can servemany useful functions and have many different compositions, thicknessesand properties. The coating material(s) dissolved in the SCF are solutesthat can freely penetrate space that the SCF penetrates provided theirmolecular size allows them to pass into an internal pore or fissure orcrack in a given solid particle or article and hence, can be depositedtherein. There is no concern about problems of making a viscous coatingsolution penetrate internal pores, cracks, and fissures characteristicof many solids.

Hence, when a solid substance is to be coated according to the processof the invention, adsorption of a specific coating maternal is made tooccur and/or slowly enhanced during the process disclosed herein byaltering the temperature and/or pressure of the continuous phase whichinitially consists of a SCF in which the coating material is dissolved,in an autoclave in a controlled manner. This involves a reduction in oneor both parameters at a specified rate to a specified value of bothparameters. Adsorption of molecules of the coating material by thesurface(s) to be coated is critical to the success of the processdisclosed here. If this cannot be made to occur, the coating materialwill not be deposited upon the surface of the substrate being coated.Once adsorption of coating material on the substrate to be coatedoccurs, further deposition of coating material(s) will be made to occurby continued controlled reduction of T and/or P inside the autoclaveuntil all molecules of the intended coating material originallydissolved in the SCF have been deposited on the solid surface beingcoated. Depending upon the amount of coating material initiallydissolved in the SCF, one can produce coatings that are of molecularthickness dimensions or macroscopic thickness dimensions. The coatingmay be a crystalline or amorphous phase depending upon the ability ofthe coating material to crystallize either during or after the coatingprocess. Further, it may be deemed desirable to adjust coatingconditions such that the coating material(s) deposit on the substratebeing coated in such a manner that a uniform film or coating is notproduced, but a coating of some other geometry is produced. In suchcases, the "coating" would form a unique geometric combination ofsubstrate and coating material which deviates significantly in structurefrom a conventional film coating.

Significantly, as the temperature and pressure inside the autoclave arereduced during the coating procedure, the SCF material that forms thecontinuous phase in the autoclave and initially acts as a solvent forthe substance being deposited as a coating generally passes from the SCFstate into a binary mixture of liquid and gas phase, and as the systembecomes totally depressurized, this material passes into only a gasphase. Controlled deposition of the coating material on the substratebeing coated can occur at various stages of this sequence of phasechanges depending upon the coating material used and its solubility inthe suspending medium, originally a SCF. However, the most meaningfulchange in solubility properties of the coating material as temperatureand pressure are altered occurs at or close to conditions that exist atthe boundary between the SCF state and binary mixture of liquid and gas.Controlling the rate of change in temperature and pressure in thisregion is particularly important.

Because of the versatility of the coating technology disclosed hereinand the ability of a SCF to produce a solution of precisely definedcomponents, specific T and P operating conditions required to deposit agiven coating material on a given substrate in a given form can vary butcan be defined by the person skilled in the art for each combination ofsubstrate being coated and coating material. When the active substanceto be coated is a liquid similar considerations apply although the speedof agitation has an incidence on the size of the droplets that arecoated.

In order to carry out the process of the invention, a measured weight ofsubstrate to be coated (i.e. an emulsionable liquid or preformedparticle(s) or article(s)), previously shown to be essentially insolublein the S(,F to be used and unaffected by said SCF under conditions to beused in the coating process), is placed in an autoclave equipped with anagitator and impellor able to be turned at a defined rate. The autoclaveis sealed and the agitator is started. If the substance to be coated isa solid particle, constant agitation is required but it should berelatively moderate in order to avoid any disturbance of the structuralintegrity of the particle. Agitation speeds can normally vary between200 and 400 RPM. If the substance to be coated is in the form of aliquid, the control of the agitation speed is also important because itcan be used to vary the size of the droplets of the emulsion formedbetween the supercritical fluid and the liquid active substanceinsoluble in it. Agitation speed for liquids normally ranges between 600and 1000 RPM. Since the active substance to be coated is initially in agaseous environment inside the autocalve, the agitator has no effect onthe active substance at this point. However, once the system ispressurized by introducing into the autoclave from an external source asubstance (e.g., CO₂) which is then brought to supercritical conditionsby changing temperature and/or pressure inside the autoclave, thesubstance placed in the autoclave becomes suspended in the SCF due tothe agitation provided by the agitator and impellor. Active substancessuspended in the SCF due to the agitation behave much like they aresuspended in a conventional liquid or liquid solution.

The next step is to introduce the desired coating material(s) into theautoclave as solute(s) dissolved in a SCF either by feeding into theautoclave a SCF solution of the desired coating material(s) or byplacing the coating material inside the autoclave at the time thesubstrate to be coated is placed in the autoclave either as free coatingmaterial or coating material contained in a molecularly porous sac. Ifthe coating material is placed in the autoclave in any manner,pressurization of the interior of the autoclave to produce a SCF statecauses the coating material(s) present inside the autoclave to bedissolved in the SCF. In order to assure that the coating material hasbeen solubilized, the system is equilibrated a finite time (e.g., 1 hr)before the coating process is continued.

Once a finite concentration of coating material(s) has been establishedin the SCF phase of the autoclave, temperature and/or pressure insidethe autoclave are altered in a controlled manner so that solubility ofthe coating material(s) present in the initial SCF is gradually reduced,continuous agitation being maintained throughout this process. As arule, such alteration involves reducing either the temperature orpressure in a controlled manner. Regardless of how this is accomplished,as solubility of the coating material(s) in the suspending phase of theautoclave decreases, affinity of said material(s) for the surface of thesubstrate being coated increases and they increasingly become adsorbedthere. If solubility of the desired coating material(s) in thesuspending phase is reduced at a sufficiently slow rate, the coatingmaterial(s) is transferred completely from the suspending phase onto thesurface of the substrate being coated thereby forming a coating. Saidcoating can be deposited so that it follows the geometric shape of thesubstrate being coated to thereby form what is commonly termed aconformational coating. Irregularly shaped particles and articles can beso coated, so the process does not require the substrate to have aregular (e.g., spherical or sphere-like) geometry. Further, thickness ofsaid coating can vary from molecular to macroscopic dimensions. Ofcourse, by the time that deposition of the desired coating material(s)on the intended substrate is complete, the operating parameters of thesystem may be so changed that the suspending fluid is no longer a SCF,but has been transformed into a liquified state which is in equilibriumwith its gaseous state. Phase diagrams that illustrate specificconditions under which these different phases exist have beenestablished for a variety of SCF systems.

Once deposition of the desired coating material(s) is complete, thesystem is depressurized and the coated particle(s) or article(s) areisolated by removing them from the autoclave.

A complete schematic version of a preferred embodiment of the apparatusof the present invention is illustrated in FIG. 1. Referring now to FIG.1, the pressured gas bottle is connected to valve 1 which delivers thegas to condenser C-1, where it is liquified. The condensed liquified gasis stored in the reservoir R-1. This liquified gas can be fed to thereservoir R-2 using valve V2. The gas phase existing in the reservoirR-1 can also be transferred to the reservoir R-2 via valve V3.

The reservoir R-2 can be used as a reaction flask and is equipped with amagnetic transmission stirrer.

The liquified gas can also be tranferred via the condenser C-2 to thepump P-1. From P-1, fluid can be fed back to reservoir via valve V4 andthe condenser C-1.

Alternately, from the pump P-1, the fluid can be heated by the heatexhanger H-1 and fed to the reservoir R-2 via valve V5, or fod to thebottom side of reservoir R-3 via valve V-6, or to the top side ofreservoir R-3 via valve V-7.

Liquids, solutions, fluids, subcritical fluid or supercritical fluidexisting in reservoir R-2 can be taken out and transferred via valve V-8by the pump P-2. Inversely, substances stored in pump P-2 can beintroduced back inside reservoir R-2, via valve V-8. Pump P-2 can alsobe used to transfer materials from the reservoir R-2 via the heatexchanger H-2 to reservoir R-3 via valve V9. Possibly, valve V10 can beused to equilibrate the pressure between the pump P-2 circuit and thereservoir R-2.

Reservoir R-2 can be used as reaction flask for coating particles, fordissolving substances, for particles formations, for emulsions, forcoacervation, for precipitation, for coprecipitation, forcristallisation, for desolvatation, for polymerization, for interfacialpolymerisation, for polycondensation . . . . The same operation can bedone in reservoir R-3, or both reservoirs can be used in the same time,or inturn of each others, or in combination to each others. ReservoirR-3 and its heating or cooling jacket is designed to create gradient oftemperature and density inside, thus assuming, if necessary, an internalturbulence in the fluid during experimental conditions.

Contents of reservoir R-2 can be fed via valve V11 to the pressurecontrolling valve V12. In a similar way, the reservoir R-3 is alsobranched via V13 or V14 to the pressure controlling valve V12. Valve V12is used to control the pressure during operations. From V12, via theheat exchanger H-3, the fluid can be decompressed in the separator S-1.From the separator S1, the gas phase can be recycled via V15 back to thereservoir R-1. All containers are equipped with a pressure jauge (PJ),an exhaut valve to atmosphere (Vair) and, or, drain valves (Vdrain).

Each reservoir and separator are equipped with separated cooling andheating jacket (TC) giving the possibility to obtain varioustemperatures at different places of the apparatus. The apparatus is alsoequipped with several windows in oder to see inside containers and withthe necessary security valves and filtering devices not shown on thefigure.

EXAMPLE 1

1.3 g Gelucire 50/02, an inert excipient derived from naturalhydrogenated food-grade fats and oils (Source: Gattefosse S.A., F-69800Saint Priest, France) is placed in a sealed sac formed from coffeefilter paper, said sac then being attached to the shaft of the agitatorplaced in an autoclave (1.5 L capacity). 3.0 g HPMCP-55 (Source:Eastman, Kingsport, Tenn., USA) is then added to the autoclave as a freepowder. The autoclave is sealed, agitation is initiated (430 RPM), andthe interior of the autoclave is pressurized by addition of CO₂ to theautoclave. Once the autoclave is pressurized by the CO₂, the temperatureof the contents of the autoclave is increased to 35° C. At this pointthe pressure of the interior of the autoclave is 110 bar, so CO₂ insidethe autoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the Gelucire 50/02initially inside the sac sufficient time to dissolve in the SCF andmigrate into the volume of the autoclave in which the particles ofHPMCP-55 are suspended in the SC CO₂. The temperature of the sealedautoclave is then slowly reduced to 27° C. at an essentially linear rateover a 17 min period from 35° C. thereby causing the SC CO₂ suspendingphase to become a mixture of liquid and gaseous CO₂, said particles ofHPMCP-55 being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of HPMCP-55 coated with a component of the Gelucire 50/02(Gelucire 50/02 is a mixture of components, so the SCF process usedselectively dissolves only certain components of the initial Gelucire50/02 sample, in this case said components have a melting range of35-40° C. as shown by differential scanning calorimetry analysis of thecoated particles. When the coated HPMCP-55 particles are placed in pH 10buffer and observed microscopically, it is found that they dissolve at asignificantly slower rate than uncoated HPMCP-55 due to the presence ofthe coating components extracted from Gelucire 50/02 that were depositedon the various surfaces of said particles by the SCF coating process.

EXAMPLE 2

1.3 g Gelucire 50/02, an inert excipient derived from naturalhydrogenated food-grade fats and oils (Source: Gattefosse S. A., F-69800Saint Priest, France) is placed in a sealed sac formed from coffeefilter paper, said sac then being attached to the shaft of the agitatorplaced in an autoclave (1.5 L capacity).

3.0 g bovine serum albumin (BSA) (Source: Sigrria, St. Louis, Mo., USA)is then added to the autoclave as a free powder. The autoclave issealed, agitation is initiated (440 RPM), and the interior of theautoclave is pressurized by addition of CO₂ to the autoclave. Once theautoclave is pressurized by the CO₂, the temperature of the contents ofthe autoclave is increased to 35° C. At this point the pressure of theinterior of the autoclave is 110 bar, so CO₂ inside the autoclave is inthe SCF state. The system is allowed to equilibrate under theseconditions for 1 hr in order to allow the Gelucire 50/02 initiallyinside the sac sufficient time to dissolve in the SCF and migrate intothe volume of the autoclave in which the particles of BSA are suspendedin the SC CO₂. The temperature of the sealed autoclave is then reducedto 27° C. by cooling at an essentially linear rate over a 17 min periodfrom 35° C. thereby causing the SC CO₂ suspending phase to become amixture of liquid and gaseous CO₂, said particles of BSA being nowsuspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles of BSA coatedwith a component of the Gelucire 50/02 (Gelucire 50/02 is a mixture ofcomponents melting, so the SCF process used selectively dissolves onlycertain components of the initial Gelucire 50/02 sample, in this casesaid components have a melting range of 35-40° C. as shown bydifferential scanning calorimetry analysis of the coated particles. WhenIS the coated BSA particles are placed in water and observedmicroscopically, it is found that they dissolve at a slower rate thanuncoated BSA due to the presence of coating material derived byextracting components from Gelucire 50/02, said components beingdeposited on the various surfaces of said particles by the SCF coatingprocess disclosed.

FIG. 2A shows the starting material (BSA) observed under opticalmicroscope. It can be seen that BSA appears as thin transparent plates.FIG. 2B shows the BSA sample after treatment with Gelucire 50/02 used asthe coating material. The sample is covered by a thin layer of gelucireand become opaque to the light.

EXAMPLE 3

1.3 g Gelucire 50/02, an inert excipient derived from naturalhydrogenated food-grade fats and oils (Source: Gattefosse S. A., F-69800Saint Priest, France) is placed in a sealed sac formed from coffeefilter paper, said sac then being attached to the shaft of the agitatorplaced in an autoclave (1.5 L capacity).

3.0 g hemoglobin (Hb) (Source: Sigma, St. Louis, Mo., USA) is then addedto the autoclave as a free powder. The autoclave is sealed, agitation isinitiated (460 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. At this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe Gelucire 50/02 initially inside the sac sufficient time to dissolvein the SCF and migrate into the volume of the autoclave in which theparticles of Hb are suspended in the SC CO₂. The temperature of thesealed autoclave is then slowly reduced to 27° C. at an essentiallylinear rate over a 17 min period from 35° C. thereby causing the SC CO₂suspending phase to become a mixture of liquid and gaseous CO₂, saidparticles of Hb being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of Hb coated with a component of the Gelucire 50/02 (Gelucire50/02 is a mixture of components, so the SCF process used selectivelydissolves only certain components of the initial Gelucire 50/02 sample,in this case said components have a melting range of 35-40° C. as shownby differential scanning calorimetry analysis of the coated particles.When the coated Hb particles are placed in water and observedmicroscopically, it is found that they dissolve at a significantlyslower rate than uncoated Hb due to the presence of the Gelucire 50/02coating deposited on the various surfaces of said particles by the SCFcoating process.

EXAMPLE 4

1.3 g Gelucire 50/02, an inert excipient derived from naturalhydrogenated food-grade fats and oils (Source: Gattefosse S. A., F-69800Saint Priest, France) is placed in a sealed sac formed from coffeefilter paper, said sac then being attached to the shaft of the agitatorplaced in an autoclave (1.5 L capacity).

3.0 g erythrosine E (Source: Sigma, St. Louis, Mo., USA) is then addedto the autoclave as a free powder. The autoclave is sealed, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. At this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe Gelucire 50/02 initially inside the sac sufficient time to dissolvein the SCF and migrate into the volume of the autoclave in which theparticles of erythrosine E are suspended in the SC CO₂. The temperatureof the sealed autoclave is then slowly reduced to 27° C. at anessentially a linear rate over a 17 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of erythrosine E being now suspended in theformer. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of erythrosine E coated with acomponent of the Gelucire 50/02 (Gelucire 50/02 is a mixture ofcomponents, so the SCF process used selectively dissolves only certaincomponents of the initial Gelucire 50/02 sample, in this case saidcomponents have a melting range of 35-40° C. as shown by differentialscanning calorimetry analysis if the coated particles. When the coatederythrosine E particles are placed in water and observedmicroscopically, it is observed that they dissolve at a significantlyslower rate than uncoated erythrosine E due to the presence of thecoating deposited on the various surfaces of said particles by the SCFcoating process.

EXAMPLE 5

1.3 g Gelucire 50/02, an inert excipient derived from naturalhydrogenated food-grade fats and oils (Source: Gattefosse S. A., F-69800Saint Priest, France) is placed in a sealed sac formed from coffeefilter paper, said sac then being attached to the shaft of the agitatorplaced in an autoclave (1.5 L capacity).

3.0 g Juvamine, a commercial vitamin C formulation that containsprimarily sucrose (Source: SED, Paris, France ) is then added to theautoclave as a free powder. The autoclave is sealed, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. At this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe Gelucire 50/02 initially inside the sac sufficient time to dissolvein the SCF and migrate into the volume of the autoclave in which theparticles of Juvamine are suspended in the SC CO₂. The temperature ofthe sealed autoclave is then slowly reduced to 27° C. at an essentiallylinear rate over a 17 min period from 35° C. thereby causing the SC CO₂suspending phase to become a mixture of liquid and gaseous CO₂, saidparticles of Juvamine being now suspended in the former. The autoclaveis subsequently slowly depressurized to atmospheric pressure to yieldparticles of Juvamine coated with a component of the Gelucire 50/02(Gelucire 50/02 is a mixture of components, so the SCF process usedselectively dissolves only certain components of the initial Gelucire50/02 sample, in this case said components have a melting range of35-40° C. as shown by differential scanning calorimetry analysis of thecoated particles. When the coated Juvamine particles are placed in waterand observed microscopically, it is found that they dissolve at asignificantly slower rate than uncoated particles due to the presence ofthe coating of the Gelucire 50/02 components deposited on the varioussurfaces of said particles by the SCF coating process.

FIG. 3 shows a sample Juvamine covered by a thin layer of Gelucire 50/02after 5 minutes in water. It can be seen that when the core materials isdissolved it remains a shell of gelucire which has the same shape as thecovered cristal. In the central part of the picture, such shell wasdestroyed under the microscope by mechanical action of needle. It can beseen from the remaining material that the shell is formed by a very thinlayer of gelucire.

EXAMPLE 6

5.0 g beeswax is placed in a sealed sac formed from coffee filter paper,said sac then being attached to the shaft of the agitator placed in anautoclave (1.5 L capacity). 2.0 BSA (Source: Sigma, St. Louis, Mo., USA) is then added to the autoclave as a free powder. The autoclave issealed, agitation is initiated (440 RPM), and the interior of theautoclave is pressurized by addition of CO₂ to the autoclave. Once theautoclave is pressurized by the CO₂, the temperature of the contents ofthe autoclave is increased to 35° C. At this point the pressure of theinterior of the autoclave is 110 bar, so CO₂ inside the autoclave is inthe SCF state. The system is allowed to equilibrate under theseconditions for 1 hr in order to allow the Gelucire 50/02 initiallyinside the sac sufficient time to dissolve in the SCF and migrate intothe volume of the autoclave in which the particles of BSA are suspendedin the SC CO₂. The temperature of the sealed autoclave is then slowlyreduced to 27° C. at an essentially linear rate over a 17 min periodfrom 35° C. thereby causing the SC CO₂ suspending phase to become amixture of liquid and gaseous CO₂, said particles of BSA being nowsuspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles of BSA coatedwith a component of the beeswax (beeswax is a mixture of components, sothe SCF process used selectively dissolves only certain components ofthe initial beeswax sample, in this case said components have a meltingrange of 35-45° C. as shown by differential scanning calorimetryanalysis of the coated particles). When the coated BSA particles areplaced on a glass slide and a drop of water is dropped on the particleson the slide, microscopic observation established that the coated BSAparticles dissolved at a significantly slower rate than uncoated BSAparticles due to the coating of the beeswax components deposited on thevarious surfaces of said particles by the SCF coating process. Indeed,it appeared that little BSA dissolved during an observation period of5-10 min.

FIG. 4 shows BSA covered by a thin layer of beeswax. It can be seen thatthis sample is floating of the top a water. drop. This. shows the strongwettability difference existing between the treated sample and thestarting material. Indeed the untreated starting material is completelysoluble in water and thus can not stay on the surface of a water drop.

EXAMPLE 7

2.0 g paraffin wax 52-54 (Source: RP Prolabo, Paris, France) is placedin a sealed sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 3.0 BSA (Source: Sigma, St. Louis, Mo., USA ) is then addedto the autoclave as a free powder. The autoclave is sealed, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. At this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe paraffin wax 52-54 initially inside the sac sufficient time todissolve in the SCF and migrate into the volume of the autoclave inwhich the particles of BSA are suspended in the SC CO₂. The temperatureof the sealed autoclave is then slowly reduced to 27° C. at anessentially linear rate over a 17 min period from 35° C. thereby causingthe SC CO₂ suspending phase to become a mixture of liquid and gaseousCO₂, said particles of BSA being now suspended in the former. Theautoclave is subsequently slowly depressurized to atmospheric pressureto yield particles of BSA coated with a component of the paraffin wax52-54 (paraffin wax 52-54 is a mixture of components, so the SCF processused selectively dissolves only certain components of the initialparaffin wax 52-54 sample), in this case said components have a meltingrange of 50-52° C. as shown by differential scanning calorimetryanalysis of the coated particles. When the coated BSA particles areplaced on a glass slide and a drop of water is dropped on the particleson the slide, microscopic observation established that the coated BSAparticles were wetted with much more difficulty than uncoated BSAparticles due to the presence of the paraffin 52-54 components depositedon the various surfaces of said particles by the SCF coating process.

EXAMPLE 8

5.0 g of the triglyceride of myristic acid, sold as Dynasan 114 (Source:Huls Aktiengellschaft, D-W-4370 Marl, Germany) is placed in a sealed sacformed from coffee filter paper, said sac then being attached to theshaft of the agitator placed in an autoclave (1.5 L capacity). 1.5 gbovine serum albumin (BSA) (Source: Sigma, St. Louis, Mo., USA) is thenadded to the autoclave as a free powder. The autoclave is sealed,agitation is initiated (440 RPM), and the interior of the autoclave ispressurized by addition of CO₂ to the autoclave. Once the autoclave ispressurized by the CO₂, the temperature of the contents of the autoclaveis increased to 35° C. At this point the pressure of the interior of theautoclave is 110 bar, so CO₂ inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the Dynasan 114 initially inside the sac sufficient timeto dissolve in the SCF and migrate into the volume of the autoclave inwhich the particles of BSA are suspended in the SC CO₂. The temperatureof the sealed autoclave is then reduced to 27° C. by cooling at anessentially linear rate over a 17 min period from 35° C. thereby causingthe SC CO₂ suspending phase to become a mixture of liquid and gaseousCO₂, said particles of BSA being now suspended in the former. Theautoclave is subsequently slowly depressurized to atmospheric pressureto yield particles of BSA coated with a component of the Dynasan 114sample used(it contains a mixture of components, so the SCF process usedselectively dissolves only certain components of the initial Dynasan 114sample), in this case said components have a melting range of 50-55° C.as shown by differential scanning calorimetry analysis of the coatedparticles.

When the coated BSA particles are placed in water and observedmicroscopically, it is found that they were more difficult to wet thanuncoated BSA due to the presence of the Dynasan 114 components depositedon the various surfaces of said particles by the SCF coating processdisclosed.

EXAMPLE 9

5.0 g of stearic acid (Source: Merck, Schuchardt, Germany) is placed ina sealed sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 3 g bovine serum albumin (BSA) (Source: Sigma, St. Louis,Mo., USA) is then added to the autoclave as a free powder. The autoclaveis sealed, agitation is initiated (450 RPM), and the interior of theautoclave is pressurized by addition of CO₂ to the autoclave. Once theautoclave is pressurized by the CO₂, the temperature of the contents ofthe autoclave is increased to 35° C. At this point the pressure of theinterior of the autoclave is 110 bar, so CO₂ inside the autoclave is inthe SCF state. The system is allowed to equilibrate under theseconditions for 1 hr in order to allow the srearic acid initially insidethe sac sufficient time to dissolve in the SCF and migrate into thevolume of the autoclave in which the particles of BSA are suspended inthe SC CO₂. The temperature of the sealed autoclave is then reduced to27° C. by cooling at an essentially linear rate over a 17 min periodfrom 35° C. thereby causing the SC CO₂ suspending phase to become amixture of liquid and gaseous CO₂, said particles of BSA being nowsuspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles of BSA coatedwith a component of the stearic acid sample used (it contains a mixtureof components, so the SCF process used selectively dissolves onlycertain components of the initial stearic acid sample), in this casesaid components have a melting range of 50-55° C. as shown bydifferential scanning calorimetry analysis of the coated particles. Whenthe coated BSA particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated BSA due to the presence of the stearic acid componentsdeposited on the various surfaces of said particles by the SCF coatingprocess disclosed.

EXAMPLE 10

2.0 g of stearyl alcohol (Source: Janssen, Belgium) is placed in asealed sac formed from coffee filter paper, said sac then being attachedto the shaft of the agitator placed in an autoclave (1.5 L capacity). 3g bovine serum ablbumin (BSA) (Source: Sigma, St. Louis, Mo., USA) isthen added to the autoclave as a free powder. The autoclave is sealed,agitation is initiated (440 RPM), and th e interior of the autoclave ispressurized by addition of CO₂ to the autoclave. Once the autoclave ispressurized by the CO₂, the temperature of the contents of the autoclaveis increased to 35° C. At this point the pressure of the interior of theautoclave is 110 bar, SO CO₂ inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the Gelucire 50/13 initially inside the sac sufficienttime to dissolve in the SCF and migrate into the volume of the autoclavein which the particles of BSA are suspended in the SC CO₂. Thetemperature of the sealed autoclave is then reduced to 27° C. by coolingat an essentially linear rate over a 17 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of BSA being now suspended in the former.The autoclave is subsequently slowly depressurized to atmosphericpressure to yield particles of BSA coated with a component of thestearyl alcohol sample used (it contains a mixture of components, so theSCF process used selectively dissolves only certain components of theinitial stearyl alcohol sample), in this case said components have amelting range of 52-62° C. as shown by differential scanning calorimetryanalysis of the coated particles. When the coated BSA particles areplaced in water and observed microscopically, it is found that they aremore difficult to wet than than uncoated BSA due to the presence of thestearyl alcohol components deposited on the various surfaces cf saidparticles by the SCF coating process disclosed.

EXAMPLE 11

2.0 g paraffin wax 52-54 (Source:RP Prolabo, Paris, France) is placed ina sealed sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 3.0 g hemoglobin (Hb) (Source: Sigma, St. Louis, Mo., USA) isthen added to the autoclave as a free powder. The autoclave is sealed,agitation is initiated (240 RPM), and the interior of the autoclave ispressurized by addition of CO₂ to the autoclave. Once the autoclave ispressurized by the CO₂, the temperature of the contents of the autoclaveis increased to 35° C. At this point the pressure of the interior of theautoclave is 110 bar, so CO₂ inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the paraffin wax 52 initially inside the sac sufficienttime to dissolve in the SCF and migrate into the volume of the autoclavein which the particles of Hb are suspended in the SC CO₂. Thetemperature of the sealed autoclave is then slowly reduced to 27° C. atan essentially linear rate over a 17 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of Hb being now suspended in the former. Theautoclave is subsequently slowly depressurized to atmospheric pressureto yield particles of Hb coated with a component of the paraffin wax52-54 (paraffin wax 52-54 is a mixture of components, so the SCF processused selectively dissolves only certain components of the initialparaffin wax 52-54 sample), in this case said components have a meltingrange of 50-52° C. as shown by differential scanning calorimetryanalysis of the coated particles. When the coated Hb particles areplaced in water and observed microscopically, it is found that they aremore difficult to wet than uncoated Hb due to the presence of theparaffin wax 52-54 components deposited on the various surfaces of saidparticles by the SCF coating process. Numerous flat plates and needlesof crystalline paraffin 52-54 were attached to the Hb particles in sucha manner that they grew away from the Hb particles in essentially aperpendicular direction.

EXAMPLE 12

2.0 g paraffin wax 52 (Source: RP Prolabo, Paris, France) is placed in asealed sac formed from coffee filter paper, said sac then being attachedto the shaft of the agitator placed in an autoclave, (1.5 L capacity).3.0 g Juvamine, a commercial mixture of vitamin C and primarily sucrose(Source: SED, Paris, France) is then added to the autoclave as a freepowder. The autoclave is sealed, agitation is initiated (440 RPM), andthe interior of the autoclave is pressurized by addition Of CO₂ to theautoclave. Once the autoclave is pressurized by the CO₂, the temperatureof the contents of the autoclave is increased to 35° C. At this pointthe pressure of the interior of the autoclave is 110 bar, SO CO₂ insidethe autoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the paraffin wax 52initially inside the sac sufficient time to dissolve in the SCF andmigrate into the volume of the autoclave in which the particles ofJuvamine are suspended in the SC CO₂. The temperature of the sealedautoclave is then slowly reduced to 27° C. at an essentially linear rateover a 17 min period from 35° C. thereby causing the SC CO₂ suspendingphase to become a mixture of liquid and gaseous CO₂, said particles ofJuvamine being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of Juvamine coated with a component of the paraffin wax 52-54(paraffin wax 52-54 is a mixture of components, so the SCF process usedselectively dissolves only certain components of the initial paraffinwax 52-54 sample), in this case said components are shown to have amelting range of 50-52° C. as shown by differential scanning calorimetryanalysis of the coated particles. When the coated Juvamine particles areplaced in water and observed microscopically, it is found that they aremore difficult to wet than uncoated Juvamine due to the presence of theparaffin wax 52-54 components deposited on the surface of said particlesby the SCF coating process. When the contents of the coated particles ofthe Juvamine sample have completely dissolved in water, there is left afragile shell of water-insoluble coating material that retains thegeometry and external structure of uncoated crystals of sucrose, theprimary component of Juvamine.

EXAMPLE 13

5.0 g beeswax (Source: APIS Centre Liegeois, VISE, Belgium) is placed ina scaled sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 1.9 g hemoglobin (Hb) (Source: Sigma, St. Louis, Mo., USA) isthen added to the autoclave as a free powder. The autoclave is scaled,agitation is initiated (220 RPM), and the interior of the autoclave ispressurized by addition of CO₂ to the autoclave. Once the autoclave ispressurized by the CO₂, the temperature of the contents of the autoclaveis increased to 35° C. At this point the pressure of the interior of theautoclave is 110 bar, so CO₂ inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the beeswax initially inside the sac sufficient time todissolve in the SCF and migrate into the volume of the autoclave inwhich the particles of hemoglobin are suspended in the SC CO₂ . Thetemperature of the scaled autoclave is then slowly reduced to 27° C. atan essentially linear rate over a 17 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of hemoglobin being now suspended in theformer. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of hemoglobin coated with acomponent of the beeswax (beeswax is a mixture of components, so the SCFprocess used selectively dissolves only certain components of theinitial beeswax sample). When the coated hemoglobin particles are placedin water and observed microscopically, it is found that they are moredifficult to wet than uncoated hemoglobin due to the presence of thebeeswax components deposited on the surface of said particles by the SCFcoating process. FIG. 5 shows said coated hemoglobin particles standingon the surface of a water drop. The uncoated starting material(hemoglobin) did not behave this way because it is immediatly dissolvedinto the water drop.

EXAMPLE 14

5.0 g beeswax (Source: APIS Centre Liegeois, VISE, Belgium) is placed ina scaled sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 2.0 g Juvamine, a commercial mixture of vitamin C andprimarily sucrose (Source: SED, Paris, France) is then added to theautoclave as a free powder. The autoclave is sealed, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. AT this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe beeswax initially inside the sac sufficient time to dissolve in theSCF and migrate into the volume of the autoclave in which the particlesof Juvamine are suspended in the SC CO₂. The temperature of the scaledautoclave is then slowly reduced to 25° C. at an essentially linear rateover a 20 min period from 35° C. thereby causing the SC CO₂ suspendingphase to become a mixture of liquid and gaseous CO₂, said particles ofJuvamine being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of Juvamine coated with a component of the beeswax (beeswax isa mixture of components, so the SCF process used selectively dissolvesonly certain components of the initial beexwas sample). When the coatedJuvamine particles are placed in water and observed microscopically, itis found that they are more difficult to wet than uncoated Juvamine dueto the presence of the beeswas components deposited on the surface ofsaid particles by the SCF coating process. When the contents of thecoated particles of the Juvamine sample have completely dissolved inwater, there is left a fragile shell of water-insoluble coating materialthat retains the geometry and external structure of uncoated crystals ofsucrose, the primary component of Juvamine. On FIG. 6 the left partshows untreated strating material and the beeswax coated sample isplaced on the right part of the picture. This is a picture obtainedunder the microscope. When a drop of water is placed in such a way thatit covers both samples at the same time, it can been seen (FIG. 7) thatafter 15 sec the cristals of the left are under dissolution while at theright the water does not dissolve the sample with the same velocity. TheFIG. 8 shows the same samples after 2 minutes under the water drop, itis clear that the starting cristals are completely dissolved (on theleft) and that the coated cristals (at the right) are not yet completelybe dissolved.

EXAMPLE 15

5.0 g beeswax (Source: APIS Centre Liegeois, VISE, Belgium) is placed ina scaled sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 12 g acetaminophen is then added to the autoclave as a freepowder. The autoclave is scaled, agitation is initiated (220 RPM), andthe interior of the autoclave is pressurized by addition of CO₂, thetemperature of the contents of the autoclave is increased to 35° C. Atthis point the pressure of the interior of the autoclave is 110 bar, soCO₂ inside the autoclave is in the SCF: state. The system is allowed toequilibrate uner these conditions for 1 hr in order to allow the beexwaxinitially inside the sac sufficient time to dissolve in the SCF andmigrate into the volume of the autoclave in which the particles ofacetaminophen are suspended in the SC CO₂. The temperature of the scaledautoclave is then slowly reduced to 27° C. at an essentially linear rateover a 17 min period from 35° C. thereby causing the SC CO₂ suspendingphase to become a mixture of liquid and gaseous CO₂, said particles ofacetaminophen being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of acetaminophen coated with a component of the beeswax(beeswax is a mixture of components, so the SCF process used selectivelydissolves only certain components of the initial beeswax sample). Whenthe coated acetaminophen particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated acetaminophen due to the presence of the beeswax componentsdeposited on the surface of said particles by the SCF coating process.When the coated acetaminophen particles are tasted orally, a significanttaste making effect is obtained.

EXAMPLE 16

5.0 g white beeswax (Source: Cooperation Pharmaceutique Française,Melun, France) is placed in a scaled sac formed from coffee filterpaper, said sac then being attached to the shaft of the agitator placedin an autoclave (1.5 L capacity). 2.0 g Juvamine, a commercial mixtureof vitamin C and primarily sucrose (Source: SED, Paris, France) is thenadded to the autoclave as a free powder. The autoclave is scaled,agitation is initiated (440 RPM) and the interior of the autoclave ispressurized by addition of CO₂ to the autoclave. Once the autoclave ispressurized by the CO₂, the temperature of the contents of the autoclaveis increased to 35° C. At this point the pressure of the interior of theautoclave is 110 bar, so CO₂ inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the white beeswax initially inside the sac sufficienttime to dissolve in the SCF and migrate into the volume of the autoclavein which the particles of Juvamine are suspended in the SC CO₂. Thetemperature of the sealed autoclave is then slowly reduced to 25° C. atan essentially linear rate over a 20 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of Juvamine being now suspended in theformer. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of Juvamine coated with acomponent of the white beeswax (white beeswax is a mixture ofcomponents, so the SCF. process used selectively dissolves only certaincomponents of the initial white beeswax sample). When the coatedJuvamine particles are placed in water and observed microscopically, itis found that they are more difficult to wet than uncoated Juvamine dueto the presence of the white beeswax components deposited on the surfaceof said particles by the SCF coating process. When the contents of thecoated particles of the Juvamine sample have completely dissolved inwater, there is left a fragile shell of water-insoluble coating materialthat retains the geometry and external structure of uncoated crystals ofsucrose, the primary component of Juvamine.

EXAMPLE 17

5.0 g white beeswax (Source: Cooperation Pharmaceutique Française,Melun, France) is placed in a scaled sac formed from coffee filterpaper, said sac then being attached to the shaft of the agitator placedin anres Lestrem, France) is then added to the autoclave as a freepowder. the autoclave is scaled, agitation is initiated (440 RPM), andthe interior of the autoclave is pressurized by addition of CO₂ to theautoclave. Once the autoclave is pressurized by the CO₂, the temperatureof the contents of the autoclave is increased to 35° C. At this pointthe pressure of the interior of the autoclave is 110 bar, so CO₂ insidethe autoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the white beeswaxinitially inside the sac sufficient time to dissolve in the SCF andmigrate into the volume of the autoclave in which the particles ofXylitol are suspended in the SC CO₂. The temperature of the sealedautoclave is then slowly reduced to 25° C. at an essentially linear rateover a 20 min period from 35° C. thereby causing the SC CO₂ suspendingphase to become a mixture of liquid and gaseous CO₂, said particles ofXylitol being now suspended in the former. The autoclave is subsequentlyslowly depressurized to atmospheric pressure to yield particles ofXylitol coated with a component of the white beeswax (white beeswax is amixture of components, so the SCF process used selectively dissolvesonly certain components of the initial white beeswax sample). When thecoated Xylitol particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated Xylitol due to the presence of the white beeswax componentsdeposited on the surface of said particles by the SCF coating process.

EXAMPLE 18

5.1 g white beeswax (Source: Cooperation Pharmaceutique Française,Melun, France) is placed in a scaled sac formed from coffee filterpaper, said sac then being attached to the shaft of the agitator placedin an autoclave (1.5 L capacity). 2.0 g potassium chloride (Source :Cooperation Pharmaceutique Française, Melun, France) is then added tothe autoclave as a free powder. The autoclave is sealed, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 35° C. At this point the pressure of the interior of the autoclave is110 bar, so CO₂ inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe white beeswax initially inside the sac sufficient time to dissolvein the SCF and migrate into the volume of the autoclave in which theparticles of potassium chloride are suspended in the SC CO₂. Thetemperature of the scaled autoclave is then slowly reduced to 25° C. atan essentially linear rate over a 20 min period from 35° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of potassium chloride being now suspended inthe former. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of potassium chloride coatedwith a component of the white beeswax (white beeswax is a mixture ofcomponents, so the SCF process used selectively dissolves only certaincomponents of the initial white beeswax sample). When the coatedpotassium chloride particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated potassium chloride due to the presence of the white beeswaxcomponents deposited on the surface of said particles by the SCF coatingprocess.

EXAMPLE 19

0.842 g Myvacct 7-07 (Source: Eastman Chemical Company, Kingsport, Tenn.37662 U.S.A.) is place in a scaled sac formed from coffee filter paper,said sac then being attached to the shaft of the agitator placed in anautoclave (1.5 L capacity). 5 g acetaminophen is then added to theautoclave as a free powder. The autoclave is scaled, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byadditon of CO₂ to the autoclave is increased to 35° C. At this point thepressure of the interior of the autoclave is 115 bar, so CO₂ inside theautoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the beeswax initiallyinside the sac sufficient time to dissolve in the SCF and migrate intothe volume of the autoclave in which the particles of acetaminophen aresuspended in the SC CO₂. the temperature of the scaled autoclave is thenslowly reduced to 27° C. at an essentially linear rate over a 17 minperiod from 35° C. thereby causing the SC CO₂ suspending phase to becomea mixture of liquid and gaseous CO₂, said particles of acetaminophenbeing now suspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles ofacetaminophen coated with a component of the Myvacct 7-07 (Myvacct 7-07is a mixture of components, so the SCF process used selectivelydissolves only certain components of the initial Myvacet 7-07 sample).When the coated acetaminophen particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated acetaminophen due to the presence of the Myvacet 7-07components deposited on the surface of said particles by the SCF coatingprocess.

EXAMPLE 20

4.87 g white beeswax (Source: Cooperation Pharmaceutique Française,Melun, France) is placed in a scaled sac formed from coffee filterpaper, said sac then being attached to the shaft of the agitator placedin an autoclave (1.5 L capacity). 2.0 g Gentamicin sulfate (Source:Cooperation Pharmaceutique Française, Melun, France) is then added tothe autoclave as a free powder. The autoclave is scaled, agitation isinitiated (210 RPM), and the interior of the autoclave is pressurized byaddition of CO₂ to the autoclave. Once the autoclave is pressurized bythe CO₂, the temperature of the contents of the autoclave is increasedto 45° C. At this point, the pressure of the interior of the autoclaveis 200 bar, so CO₂ inside the autoclave is in the SCF state. The systemis allowed to equilibrate under these conditions for 1 hr in order toallow the white beeswax initially inside the sac sufficient time todissolve in the SCF and migrate into the volume of the autoclave inwhich the particles of Gentamicin sulfate are suspended in the SC CO₂.the temperature of the scaled autoclave is then slowly reduced to 20° C.at an essentially linear rate over a 65 min period from 45° C. therebycausing the SC CO₂ suspending phase to become a mixture of liquid andgaseous CO₂, said particles of Gentamicin sulfate being now suspended inthe former. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of Gentamicin sulfate coatedwith a component of the white beeswax (white beeswax is a mixture ofcomponents, so the SCF process used selectively dissolves only certaincomponents of the inntial white beeswas sample). When the coatedGentamicin sulfate particles are placed in water and observedmicroscopically, it is found that they are much more difficult to wetthan uncoated Gentamicin sulfate due to the presence of the whitebeeswax components deposited on the surface of said particles by the SCFcoating process.

EXAMPLE 21

ls France, 49100 Angers, France) is placed in a scaled sac formed fromcoffee filler paper, said sac then being attached to the shaft of theagitator placed in ar autoclave (1.5 L capacity). 2.0811 gD,L-Methionine (Source: Sigma, St. Louis, Mo., USA) is then added to theautoclave as a free powder. The autoclave is scaled, agitation isinitiated (440 RPM), and the interior of the autoclave is pressurized byaddition of CO2 to the autoclave. Once the autoclave is pressurized bythe CO2, the temperature of the contents of the autoclave is increasedto 45° C. At this point the pressure of the interior of the autoclave is195 bar, so CO2 inside the autoclave is in the SCF state. The system isallowed to equilibrate under these conditions for 1 hr in order to allowthe Inwitor initially inside the sac sufficient time to dissolve in theSCF and migrate into the volume of the autoclave in which the particlesof D,L-Methionine are suspended in the SCCO2. The temperature of thescaled autoclave is then slowly reduced to 27° C. at an essentiallylinear rate over a 27 min period from 45° C. thereby causing the SC C02suspending phase to become a mixture of liquid and gaseus CO2, saidparticles of D,L-Methionine being now suspended in the former. Theautoclave is subsequently slowly depressurized to atmospheric pressureto yield particles of D,L-Methionine coated with a component of theInwitor. When the coated D,L-Methionine particles are placed in waterand observed microscopically, it is found that they are more difficultto wet than uncoated D,L-Methionine due to the presence of the Inwitorcomponents deposited on the surface of said particles by the SCF coatingprocess. Interesting taste masking is obtained.

EXAMPLE 22

ls France, 49100 Angers, France) is placed in a scaled sac formed fromcoffee filter paper, said sac then being attached to the shaft of theagitator placed in an autoclave (1.5 L capacity), 2.0085 g Xylitolres,Lestrem, France) is then added to the autoclave as a free powder. Theautoclave is scaled, agitation is initiated (440 RPM), and the interiorof the autoclave is pressurized by addition of CO2 to the autoclave.Once the autoclave is pressurized by the CO2, the temperature of thecontents of the autoclave is increased to 45° C. At this point thepressure of the interior of the autoclave is 150 bar, so CO2 inside theautoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the Inwitor initiallyinside the sac sufficient time to dissolve in the SCF and migrate intothe volume of the autoclave in which the particles of Xylitol aresuspended in the SCCO2. The temperature of the scaled autoclave is thenslowly reduced to 27° C. at an essentially linear rate over a 27 minperiod from 45° C. thereby causing the SC CO2 suspending phase to becomea mixture of liquid and gaseus CO2, said particles of Xylitol being nowsuspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles of Xylitolcoated with a component of the Inwitor. When the coated Xylitolparticles are placed in water and obseved microscopically, it is foundthat they are more difficult to wet than uncoated Xylitol due to thepresence of the Inwitor components deposited on the surface of saidparticles by the SCF coating process.

EXAMPLE 23

4.9804 g Syncrowax BB4 (Source: Croda, North Humberside UK) is placed ina scaled sac formed from coffee filter paper, said sac then beingattached to the shaft of the agitator placed in an autoclave (1.5 Lcapacity). 2,0397 g D,L-Methionine (Source: Sigma, St. Louis, Mo., USA)is then added to the autoclave as a free powder. The autoclave issealed, agitation is initiated (440 RPM) and the interior of theautoclave is pressurized by addition of CO2 to the autoclave. Once theautoclave is pressurized by the CO2, the temperature of the contents ofthe autoclave is increased to 45° C. At this point the pressure of theinterior of the autoclave is 190 bar, so CO2 inside the autoclave is inthe SCF state. The system is allowed to equilibrate under theseconditions for 1 hr in order to allow the Syncrowax initially inside thesac sufficient time to dissolve in the SCF and migrate into the volumeof the autoclave in which the particles of D,L-Methionine are suspendedin the SCCO2. The temperature of the scaled autoclave is then slowlyreduced to 27° C. at an essentially linear rate over a 27 min periodfrom 45° C. thereby causing the SC CO2 suspending phase to become amixture of liquid and gaseus CO2, said particles of D,L-Methionine beingnow suspended in the former. The autoclave is subsequently slowlydepressurized to atmospheric pressure to yield particles ofD,L-Methionine coated with a component of the Syncrowax. When the coatedD,L-Methionine particles are placed in water and observedmicroscopically, it is found that they are more difficult to wet thanuncoated D,L-Methionine due to the presence of the Syncrowax componentsdeposited on the surface of said particles by the SCF coating process.Interesting taste masking is obtained.

EXAMPLE 24

0.4567 g white beeswax (Source: Cooperation Pharmaceutique Française,Melun, France) is placed in a scaled sac formed from coffee filterpaper, said sac then being attached to the shaft of the agitator placedin an autoclave (1.5 L capacity). 2,0053 g D,L-Methionine (Source:Sigma, St. Louis, Mo., USA) is then added to the autoclave as a freepowder. The autoclave is scaled, agitation is initiated (440 RPM), andthe interior of the autoclave is pressurized by addition of CO2 to theautoclave. Once the autoclave is pressurized by the CO2, the temperatureof the contents of the autoclave is increased to 45° C. At this pointthe pressure of the interior of the autoclave is 185 bar, so CO2 insidethe autoclave is in the SCF state. The system is allowed to equilibrateunder these conditions for 1 hr in order to allow the white beeswaxinitially inside the sac sufficient time to dissolve in the SCF andmigrate into the volume of the autoclave in which the particles ofD,L-Methionine are suspended in the SCCO2. The temperature of the scaledautoclave is then slowly reduced to 27° C. at an essentially linear rateover a 27 min period from 45° C. thereby causing the SC CO2 suspendingphase to become a mixture of liquid and gaseus CO2, said particles ofD,L-Methionine being now suspended in the former. The autoclave issubsequently slowly depressurized to atmospheric pressure to yieldparticles of D,L-Methionine coated with a compoent of the white beeswax.When the coated D,L-Methionine particles are placed in water andobserved microscopically, it is found that they are more difficult towet than uncoated D,L-Methionine due to the presence of the whitebeeswax components deposited on the surface of said particles by the SCFcoating process. Interesting taste masking is obtained.

EXAMPLE 25

0.1752 g Octadecanol (Source Janssen, Beerse Belgium) is placed in ascaled sac formed from coffee filter paper, said sac being attached tothe shaft of the agitator placed in a autoclave (1.5 L capacity). 2,000g Acetylsalicylic acid (Source: Sigma, St. Louis, Mo., USA) is thenadded to the autoclave as a free powder. The autoclave is scaled,agitation is initiated (440 RPM), and the interior of the autoclave ispressurized by addition of CO2 to the autoclave. Once the autoclave ispressurized by the CO2, the temperature of the contents of the autoclaveis increased to 45° C. At this point the pressure of the interior of theautoclave is 160 bar, so CO2 inside the autoclave is in the SCF state.The system is allowed to equilibrate under these conditions for 1 hr inorder to allow the Octadecanol initially inside the sac sufficient timeto dissolve in the SCF and migrate into the volume of the autoclave inwhich the particles of Acetylsalicylic acid are suspended in the SCCO2.The temperature of the scaled autoclave is then slowly reduced to 27° C.at an essentially linear rate over a 27 min period from 45° C. therebycausing the SC CO2 suspending phase to become a mixture of liquid andgaseus CO2, said particles of Acetylsalicylic acid being now suspendedin the former. The autoclave is subsequently slowly depressurized toatmospheric pressure to yield particles of Acetylsalicylic acid coatedwith a component of the Octadecanol. When the coated Acetylsalicylicacid particles are placed in water and observed microscopically, it isfound that they are more difficult to wet than uncoated Acetylsalicylicacid due to the presence of the Octadecanol components deposited on thesurface of said particles by the SCF coating process.

REFERENCES

1. A Review, J. W. Tom and P. G. Debenedetti, J. Aerosol Sci., 22,555-584, 1991. --Particle Formation With Supercritical Fluids--

E. M. Phillips and V. J. Stella, Int. J. Pharm., 94, 1-10, 1993--RapidExpansion From Supercritical Solutions: Application To PharmaceuticalProcesses,

3. J. Bleich, B. W. Muller, and W. Wassmus, Intl. J. Pharm., 97,111-117, 1993--.Aerosol Extraction System--A New MicroparticleProduction Technique,

4. J. W. Tom and P. G. Debenedetti, Biotechnol. Prog., 7, 403-411,1991--.Formation of Bioerodible Polymeric Microspheres andMicroparticles By Rapid Expansion of Supercritical Solutions,

5. J. Supercrit. Fluids, 7, 9-29, 1994.--Precipitation of Poly(L-lacticacid) and Composite Poly(L-lactic acid)--Pyrene Particles by RapidExpansion of Supercritical Solutions,

We claim:
 1. A microparticle comprising a solid particle entrapped within a coating including a layer of coating material, whereinthe layer of said coating material is conformationally distributed on said solid particle and has a thickness ranging from the thickness of a mono-molecular layer to about 100 μm; and the coated microparticle has a diameter ranging from 20 nm to 100 μm when the solid particle has a spherical shape.
 2. The microparticle according to claim 1, wherein the thickness of said layer of coating material ranges from the thickness of a monomolecular layer to about 40 μm.
 3. The microparticle according to claim 1, wherein said solid particle is of regular but not spherical geometry or of irregular geometry, said coating material following the surface of said particle including internal pores and crevices of said solid particle.
 4. The microparticle according claim 1, wherein said coating comprises a plurality of layers of identical or different coating material.
 5. The microparticle according to claim 4, wherein the thickness of said layers is identical or different.
 6. The microparticle according to claim 1, wherein said coating material includes fatty acids, fatty alcohols, glycerides, cholesterol, waxes, lipids and natural or synthetic polymers.
 7. A composition comprising a plurality of microparticles of even or uneven size distribution comprising a solid particle conformationally entrapped within a layer of coating material having a thickness ranging from the thickness of a mono-molecular layer to about 100 μm and wherein the coated microparticle has a diameter ranging from 20 nm to 100 μm when the solid particle has a spherical shape.
 8. A process for entrapping an active substance in a coating material, said process comprising the steps of:a. suspending said active substance which is in a solid state or absorbed in a solid substrate, in a supercritical fluid containing said coating material dissolved therein under conditions which do not cause a substantial swelling or dissolution effect on said active substance if said active substance is in the solid state; and b. gradually reducing the temperature and/or pressure of said super critical fluid under controlled condition to reduce the solubility of said coating material in said supercritical fluid to cause said coating material to be deposited onto said active substance.
 9. the process according to claim 8, wherein said active substance is in the form of solid particles or dissolved in a liquid absorbed in a porous solid substrate wherein said solid particles or said porous solid substrate particles are constantly agitated during their exposure to the supercritical fluid containing the coating material dissolved therein.
 10. The process according to claim 8, wherein when said active substance is a solid particle, the conditions under which said coating material is deposited on said solid particle are chosen to maintain the physical integrity of said solid particle throughout said process by avoiding solubilization of said solid particle in said supercritical fluid.
 11. The process according to any one of claim 8, wherein said process comprises a further step in which said coating material deposited onto said active substance is cured in a controlled manner.
 12. the process according to any one of claim 8, wherein said active substance and said coating material are placed in an autoclave which is then filled with a supercritical fluid under the conditions of temperature and pressure required to dissolve said coating material in said supercritical fluid.
 13. The process according to claim 8, wherein said active substance is placed in a autoclave which is filled with a supercritical fluid containing said coating material dissolved therein.
 14. An apparatus for depositing a coating material dissolved in a supercritical fluid onto an active substance, wherein said apparatus comprises:a reservoir/reaction chamber capable of receiving and maintaining a gas under supercritical conditions, a pressurizable reaction chamber in fluid communication with said reservoir/reaction chamber, said pressurizable reaction chamber comprising stirring means to stir said active substance when said supercritical fluid containing said dissolved coating material is introduced in said reaction chamber.
 15. The apparatus according to claim 14, wherein it further comprises reservoir means in fluid communication with said supercritical gas condenser for dissolving said coating material in said supercritical fluid.
 16. The apparatus according to claim 14, which further comprises means for controlling temperature and pressure in said pressurizable reaction chamber.
 17. The apparatus according to claim 14, wherein said stirring means comprises a magnetic transmission stirrer. 